Nitrone-related therapeutics: potential of NXY-059 for the treatment of acute ischaemic stroke

At present, none of the neurodegenerative diseases such as Parkinson's disease, Alzheimer's disease and stroke are treatable with compounds that slow or halt neuronal cell death. However, the prototype nitrone radical trap alpha-phenyl-tert-butylnitrone (PBN) has been shown to be an effective neuroprotective agent in various models of neurodegeneration. Some of these data are briefly reviewed as an introduction to an examination of the effect of the novel nitrone radical trapping agent disodium 2,4-disulfophenyl-N-tert-butylnitrone (NXY-059) in various animal models of stroke. NXY-059 has been shown to be an effective neuroprotective agent in both transient (reperfusion) and permanent focal ischaemia models in rats. In both types of model, NXY-059 has a large window of opportunity, providing effective neuroprotection when given up to 5 hours after the start of the occlusion in transient ischaemia and 4 hours after the start of permanent ischaemia. The compound is also effective in a marmoset permanent ischaemia model when administered up to 4 hours after the start of the occlusion. In this model it has been found to attenuate the problem of spatial neglect and maintain function to the paretic arm. NXY-059 administration also improves motor function in a rat haemorrhagic stroke model and has a neuroprotective effect in a rabbit thromboembolic stroke model. The compound is also well tolerated in stroke patients at plasma levels shown to provide a maximum neuroprotective effect in animal models of stroke.NXY-059, like PBN, is a nitrone with free radical trapping properties and this may be the basis of its neuroprotective action. However, experiments with PBN and NXY-059 suggest the possibility of other mechanisms being involved and these are also reviewed. Further experiments are required to fully elucidate the mechanism of action of these very effective neuroprotective agents.